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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Adalimumab is effective in inducing clinical remission in patients with Crohn’s disease who lost response or became intolerant to infliximab.

Aim  To evaluate long-term efficacy and safety of adalimumab as a second line therapy in luminal and fistulizing Crohn’s disease.

Methods  We report our single-centre experience in 53 patients. We evaluated maintenance of clinical response defined as the absence of adverse events leading to drug withdrawal, no major abdominal surgery and no loss of clinical response in initial responders. Major abdominal surgery, steroid sparing, complete fistula closure and safety were also assessed.

Results  The probability of maintaining clinical response was 77.2%, 67.8% and 50.8% at 26, 52 and 130 weeks respectively. The probability of remaining major abdominal surgery-free was 82.3% at 26, 52 and 130 weeks. Complete fistula closure occurred in six of 10 patients, and eight of 10 patients were able to taper steroid therapy. Adverse events occurred in 31 patients (58.5%) leading to adalimumab withdrawal in nine patients (17%).

Conclusion  Adalimumab therapy may be effective in the long term in both luminal and fistulizing Crohn’s disease in infliximab-failure patients, half of patients maintaining clinical response and potentially avoiding major abdominal surgery in 80% of cases.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Infliximab, a chimeric monoclonal antibody to tumour necrosis factor (TNF), is effective in inducing and maintaining response and remission in patients with moderate-to-severe Crohn’s disease (CD).1 However, infliximab is immunogenic and repeated administration can result in the development of antibodies to infliximab that lead to infusion reactions, loss of efficacy and delayed hypersensitivity reactions.2–4

Two other anti-TNF agents, namely adalimumab and certolizumab (a PEGylated humanized Fab’ fragment to TNF), have proven efficacy in the treatment of CD refractory to standard medical therapy with steroids or immunomodulatory agents.5–8 Adalimumab is a recombinant human IgG1 human monoclonal antibody that binds with high affinity and specificity to human soluble TNF, but not to lymphotoxin.

A 4-week randomized placebo-controlled trial named GAIN (Gauging Adalimumab Efficacy in Infliximab Nonresponders)9 and open-label trials10–12 have demonstrated that adalimumab therapy was effective in inducing remission in patients with active CD who had previously responded to infliximab and then lost response or became intolerant. Several open-label trials13, 14 as well as an open-label extension study of the GAIN trial15 suggested that adalimumab therapy may also be effective in maintaining clinical remission at 1 year in patients with CD who lost response or became intolerant to infliximab. More recently, adalimumab as a second line therapy appeared to be effective and well tolerated in the long term.16 However, because of small size sample,13, 14, 16 no definitive conclusions can be drawn from these studies on long-term efficacy and safety of adalimumab therapy as a second line therapy. In addition, data on fistula closure at 1 year are sparse,13 while adalimumab efficacy beyond 1 year remains unknown in fistulizing CD.

We report here our single-centre experience regarding long-term efficacy and safety of adalimumab therapy for CD with lost response or intolerance to infliximab.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Selection of patients

The medical records of all patients who were treated with adalimumab therapy for CD with intolerance or lost response to infliximab at our centre (University Hospital of Nancy) were retrospectively reviewed. Patients treated with adalimumab as a first line therapy for CD were excluded from the study. Eligible patients were men or women who were at least 18 years of age. Loss of response to infliximab was defined as the presence of symptoms or evidence of disease activity as judged by their treating physician despite an increase of infliximab dosing to 10 mg/kg and/or a decrease in interval up to 4 weeks between infliximab infusions. Inability to tolerate infliximab was defined when acute or delayed hypersensitivity reactions, as judged by their treating physician, led to discontinuation of infliximab therapy. The diagnosis of CD was made at least 3 months earlier using radiological, endoscopic or histological evidence. The extent of disease and disease behaviour were defined according to Montreal classification.17 All patients had a negative PPD skin test prior to starting adalimumab.

Concomitant medications

Concurrent therapies, including 5-aminosalicylates, steroids, azathioprine, mercaptopurine, methotrexate and antibiotics were recorded. The use of immunosuppressive drugs was considered as concomitant only if it was maintained for at least 3 months from the date of study entry.

Adalimumab therapy

Pharmacist prepared 1.0 mL vials containing 40 mg/0.8 mL adalimumab. Injections of adalimumab were administered by medical staff at an on-site facility, and patients were monitored for 2 h following administration for adverse reactions. The patients received at week 0 a loading dose of 160 or 80 mg adalimumab subcutaneously followed by a 80- or 40-mg dose at week 2 and thereafter 40 mg every other week. The interval between injections was decreased to 40 mg weekly in patients who did not achieve clinical response, as judged by their treating physician.

Outcome measures

We first evaluated the percentage of patients maintaining clinical response. Maintenance of clinical response was defined as: (i) the absence of adverse events leading to drug withdrawal; (ii) no major abdominal surgery and (iii) no loss of clinical response in initial responders as judged by the physician. The percentages of patients remaining major abdominal surgery-free (major abdominal surgery was defined as intestinal resection and/or stricturoplasty), as well as steroid sparing among the patients treated with steroids (including budesonide) at baseline and complete fistula closure (evaluated by clinical examination and defined as closure of all fistulas that were draining at baseline) at last known follow-up, and safety throughout the study were also assessed.

Finally, we evaluated the proportion of patients who needed dose escalation to 40 mg weekly adalimumab during the study period.

Statistical analyses

Quantitative variables were described as mean ± standard deviation (s.d.) or as median and percentile [interquartile range (IQR): 25% and 75%] in case of abnormal distribution. Categorical variables were presented as counts and per cent of the cohort. Probabilities of the following events were analysed using the Kaplan–Meier method: clinical response during adalimumab therapy and major abdominal surgery. Time to event was analysed from the date of the first adalimumab infusion to the date of the event or last known follow-up. To search for predictive factors for loss of clinical response and major abdominal surgery, we performed univariate analysis with log-rank test. Analysis of proportions was performed using the Fischer’s exact test. A paired Student’s t-test evaluated the effect of adalimumab on complete fistula closure and steroid sparing. All analyses were performed using MedCalc (Frank Schoonjans, Mariakerke, Belgium) software packages.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Characteristics of the patients

Between March 2005 and September 2008, a total of 53 adult patients were treated with adalimumab as a second line therapy. The baseline characteristics of the patients are shown in Table 1. The mean age of our population was 35.47 years (s.d. = 12.8; range, 17–67), and the mean duration of disease was 9.32 years (s.d. = 7.06; range, 1–27). According to Montreal classification, five patients (9.4%) had pure ileal disease (L1), 16 (30.2%) had pure colonic (L2) and 32 (60.4%) had ileocolonic (L3) disease. Thirty-two patients (60.4%) had nonstricturing and nonpenetrating disease (B1), 26.4% (14/53) had structuring disease (B2) and 13.2% (seven of 53) had penetrating disease (B3). Perianal disease (p) was noted in 22 of the 53 patients (41.5%); 10 patients out of 53 (18.9%) had open and draining perianal fistulae at baseline.

Table 1.   Baseline characteristics of the 53 patients
Variablen (%)Mean (s.d.)Median (IQR)Range
  1. s.d., standard deviation; IQR, interquartile range: 25% and 75%.

Female36 (67.9)   
Age at entry (years) 35.47 (12.18) 17–67
Current smokers23 (43.4)   
Extra-intestinal manifestations21 (39.6)   
Disease duration at entry (years) 9.32 (7.06) 1–27
Location of Crohn’s disease (Montreal L)
 L1 = ileal5 (9.4)   
 L2 = colonic16 (30.2)   
 L3 = ileocolonic32 (60.4)   
 L4 = isolated upper disease1 (1.9)   
Disease behaviour (Montreal B)
 B1 = nonstricturing, nonpenetrating32 (60.4)   
 B2 = stricturing14 (26.4)   
 B3 = penetrating7 (13.2)   
p = perianal disease22 (41.5)   
Open and draining perianal fistulae10 (18.9)   
Crohn’s-related previous medications
 Corticosteroids (include budesonide)52 (98.1)   
 Azathioprine or mercaptopurine49 (92.5)   
 Methotrexate12 (22.6)   
 5-Aminosalicylates18 (34)   
Prior intestinal resection14 (26.4)   
Concomitant medications at entry
 Corticosteroids (include budesonide)10 (18.9)   
 Azathioprine or mercaptopurine17 (32.1)   
 Methotrexate1 (1.9)   
 5-Aminosalicylates0   
Number of anterior infliximab infusions  9 (4–19.25)2–40
Reason for discontinuing infliximab
 Intolerance32 (60.4)   
 Loss of response21 (39.6)   

The median number of previous infliximab infusions was 9 (IQR = 4–19.25; range, 2–40). Seventeen out of 53 patients (32.1%) were receiving azathioprine at the time of adalimumab therapy, one patient (1.9%) was on methotrexate and 10 (18.9%) were on steroids.

Twenty-one out of the 53 patients (39.6%) experienced a loss of response to infliximab that led to drug discontinuation; the remaining 32 patients (60.4%) became intolerant to infliximab therapy as defined by their treating physician.

Clinical efficacy

The mean number of adalimumab infusions was 21.77 (s.d. = 16.59; range, 1–65). Twenty-four and 29 patients received a loading dose of 80/40 or 160/80 mg adalimumab respectively. The mean duration of follow-up of patients treated with adalimumab was 43.55 weeks (s.d. = 33.19; range, 2–130).

Three (5.7%) patients were judged as primary nonresponders and underwent major abdominal surgery. A total of 18 out of 53 patients (34%) discontinued adalimumab during the study period, with a mean duration of adalimumab continuation of 50 weeks (s.d. = 34.77; range, 2–130). Seven patients (38.9%) stopped adalimumab because of noninfectious adverse events, eight (44.4%) underwent major abdominal surgery, two patients (11.1%) stopped adalimumab because of serious infectious complications (dental abscess, liver abscess) and one patient (5.6%) decided to discontinue adalimumab because she was in clinical remission after 80 weeks of treatment; accordingly, she was considered maintaining clinical response to adalimumab therapy.

At last known follow-up, 36 out of 53 patients were in clinical response with the following actuarial probabilities: 77.2% (±6.1%), 67.8% (±7.5%) and 50.8% (±10.1%) at 26, 52 and 130 weeks respectively (Figure 1).

image

Figure 1.  Probability of maintaining clinical response in the 53 patients.

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In the subgroup of patients who stopped adalimumab because of noninfectious adverse events (n = 7), adalimumab was replaced with certolizumab in five patients, azathioprine monotherapy was initiated in one patient and one patient remained in clinical remission without any medications for CD. In the two patients who presented infectious complications leading to drug withdrawal, azathioprine was introduced after full resolution of the infectious episode.

Eight out of 18 patients (44.4%) underwent major abdominal surgery during the study period. The probability of remaining major abdominal surgery-free was 82.3% (±5.7%) at weeks 26, 52 and 130 (Figure 2).

image

Figure 2.  Probability of remaining free of major abdominal surgery in the 53 patients.

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None of the variables listed in Table 1 influenced the probabilities of maintaining clinical response and remaining free of major abdominal surgery in univariate analysis.

The proportion of subjects failing to maintain clinical response during the study was broadly similar in patients treated for loss of response to infliximab (six of 21, 28.6%) and those treated for intolerance to this drug (11/32, 34.4%), with no statistical difference (P = 0.98 by log-rank test). The proportion of patients undergoing major abdominal surgery was 23.8% (five of 21) in patients who lost response to infliximab when compared to 9.4% (three of 32) in the infliximab intolerant group (P = 0.14 by log-rank test). Clinical response and major abdominal surgery rates were not influenced by the induction regimen used (160/80 vs. 80/40 mg), with P = 0.22 and P = 0.24 by log-rank test for clinical response and major abdominal surgery respectively.

Dose escalation to 40 mg weekly adalimumab

Seven out of 53 patients (13.2%) required dose escalation to 40 mg weekly treatment. Adalimumab was withdrawn in one patient following major abdominal surgery. The remaining six patients had sustained adalimumab efficacy, with a mean duration of follow-up of 57 weeks. The rates of dose escalation were broadly similar in patients who received a loading dose of 160/80 mg (three of 29, 10.3%) when compared with those who received 80/40 mg (four of 24, 16.7%), with no statistical difference (P = 0.69).

Complete fistula closure and steroid sparing

Complete fistula closure occurred in six out of 10 patients (60%) with open fistula tracts at baseline, with a sustained efficacy at last known follow-up (P = 0.0051 vs. baseline). The percentage of patients who were able to taper and discontinue steroids (prednisone or budesonide) throughout the study period was 80% (P = 0.0002 vs. baseline). None of the patients with fistulizing CD at baseline received treatment with antibiotics during the study.

Safety

All adverse events are listed in Table 2. Adverse events occurred in 31 out of 53 patients (58.5%), leading to adalimumab withdrawal in nine patients (17%); psoriasis led to drug withdrawal in three patients (5.7%), angioneurotic oedema in three individuals (5.7%), serious infections (dental abscess, liver abscess) in two patients (3.8%), and skin toxicity in one subject (1.9%). Multiple dental abscesses required dental extraction, and liver abscess had a favourable outcome after both CT-guided percutaneous drainage and antibiotic treatment. Urinary tract infection (n = 2), otitis (n = 2) and/or sinusitis (n = 1) with favourable outcome after antibiotic therapy were also reported. One patient developed herpetic keratitis with favourable outcome after oral acyclovir therapy. Ten out of 17 patients (58.8%) receiving azathioprine in combination with adalimumab developed infectious complications vs. only 13.9% (five of 36) of patients in the adalimumab monotherapy group (P = 0.0022). Importantly, all three patients who developed serious infections (liver abscess, herpetic keratitis, multiple dental abscesses) were receiving azathioprine in combination with adalimumab. Two patients without extraintestinal manifestations at baseline developed arthralgias. Arthralgias, psoriasis and infectious events were judged as possibly drug-related adverse events by the investigators. There were no deaths or malignancies. Of note, all patients who experienced noninfectious adverse events leading to drug withdrawal (n = 7) were intolerant to infliximab. Finally, among the 32 patients with prior intolerance to infliximab, adalimumab therapy was well tolerated in 62.5% of patients (20/32).

Table 2.   Adverse events in the 53 patients
Variablen (%)
Number of patients with at least one adverse event31 (58.5)
Total number of adverse events50
Number of serious adverse events10
Number of adverse events leading to adalimumab withdrawal9
Deaths or malignancy0
Adverse events Number of patients (%)Number of patients with adalimumab withdrawal
Psoriasis de novo6 (11.3)3
Injection site erythema5 (9.4)0
Headache4 (7.6)0
Flu-like symptoms3 (5.7)0
Angioneurotic oedema3 (5.7)3
Acute gastroenteritis3 (5.7)0
Arthralgias2 (3.8)0
Otitis2 (3.8)0
Pharyngitis2 (3.8)0
Pyrexia2 (3.8)0
Skin eruption2 (3.8)0
Urinary tract infection2 (3.8)0
Upper respiratory tract infection2 (3.8)0
Conjunctivitis1 (1.9)0
Herpetic keratitis1 (1.9)0
Liver abscess1 (1.9)1
Multiple dental abscesses1 (1.9)1
Onychomycosis1 (1.9)0
Oral thrush1 (1.9)0
Palpitation1 (1.9)0
Recurrent genital infection1 (1.9)0
Sinusitis1 (1.9)0
Skin toxicity1 (1.9)1
Whitlow1 (1.9)0
Furonculosis1 (1.9)0

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The development of an attenuated response or intolerance over time is a significant problem in patients with inflammatory bowel diseases treated with infliximab therapy. Adalimumab has demonstrated its efficacy in inducing clinical response in patients with CD who lost response or became intolerant to infliximab.9, 10 In contrast, long-term efficacy and safety profile of adalimumab as a second line therapy for CD remains poorly investigated. An ongoing open-label extension study assessed the long-term follow-up of infliximab-failure patients treated with adalimumab in 310 CD patients who completed the 4-week GAIN trial through 1 year of therapy.15 Adalimumab showed sustained efficacy in maintaining clinical remission and response through 1 year of therapy with two-thirds of responding patients maintaining response and 40% achieving remission. However, data on adalimumab efficacy for fistula closure have not been made public.15 In a small series of 16 patients included in an open-label single-centre study, Seiderer et al.14 investigated adalimumab induction and maintenance therapy after infliximab failure in CD. The median duration of adalimumab therapy was 27.9 weeks. Ten of 16 patients achieved remission at week 8, and 37.5% maintained remission at week 24. There was one serious complication (fungal pneumonia).14 We evaluated efficacy and safety profile of adalimumab as a second line therapy for CD in a 52-week open-label trial enrolling 24 patients. Clinical remission was achieved in 58% (14/24), steroid tapering in 75% (three of four) and complete fistula closure in 67% (three of four) of patients with no serious toxicity.13 More recently, Ho et al.16 evaluated adalimumab as a first line (n = 2) or second line (n = 20) therapy in patients with refractory CD, with a median follow-up of 1 year. The probability of maintaining clinical remission at 2 years was 68% and 67% of patients avoided the need for further surgery at 2 years censor. Fifty-nine per cent of patients required adalimumab dose escalation to 40 mg weekly. Two patients developed serious infections (colonic perforation leading to the development of psoas abscess and severe facial cellulitis), and one developed lung cancer.16 The small sample size and lack of data on fistula closure do not allow definitive conclusions.16

We report here our single-centre experience regarding long-term efficacy and safety of adalimumab therapy for CD in 53 patients with loss of response or intolerance to infliximab. The probabilities of maintaining clinical response and remaining major abdominal surgery-free were 50.8% and 82.3% at 130 weeks respectively. Of the 53 patients, eight (15%) underwent major abdominal surgery, which is consistent with previous reports.16 Importantly, complete fistula closure occurred in 60% of patients and steroid sparing was achievable throughout the study period in 80% of patients; data regarding the efficacy of adalimumab in terms of steroid-sparing and complete fistula closure should be interpreted with caution due to small sample size. Taken together, our results indicate that adalimumab as a second line therapy may be effective in both luminal and fistulizing CD in the long term. Clinical benefit in terms of clinical response and major abdominal surgery was broadly similar in patients treated for loss of response to infliximab and those treated for intolerance to this drug, confirming previous reports.15 It should be noted that dose escalation to 40 mg weekly adalimumab was required in 13.2% of patients, which is lower than that reported in two recent studies.16, 18 In the study by West et al.,18 the need for dose escalation was associated with high levels of antibodies to adalimumab. Immunogenicity, i.e. occurrence of anti-adalimumab antibodies, was not available in our cohort of patients. It should be emphasized that in our study, adalimumab dose escalation allowed continuation of anti-TNF therapy in a majority of patients.

Regarding long-term safety of adalimumab as a second line therapy, in our study, nine patients stopped adalimumab therapy because of serious adverse events with two cases of serious infectious complications. No deaths, malignant conditions, opportunistic infections, cases of tuberculosis, demyelinating diseases or lupus-like reactions were reported during this study. Interestingly, adalimumab was well tolerated in 62.5% of patients who previously experienced intolerance to infliximab. When considering the subgroup of patients who presented infectious complications on adalimumab therapy, all individuals who developed serious infectious complications (multiple dental abscesses, liver abscess and herpetic keratitis) were also receiving azathioprine for more than 3 months. Furthermore, infectious complications occurred in 58.8% in patients on combination therapy (adalimumab plus azathioprine) vs. only 13.9% in patients on adalimumab monotherapy. While rates of global adverse events reported in randomized placebo-controlled trials5, 9 were similar to that observed our study, lower rates of adverse events leading to adalimumab discontinuation and serious infections were reported in randomized placebo-controlled trials.5, 9 Our safety results might reflect daily clinical practice, even though this needs to be confirmed in larger prospective studies. Furthermore, six patients (11.3%) developed psoriasis in this study. There are numerous reports of the induction or worsening of psoriasis in patients treated with TNF antagonists.19 An aggressive treatment of the skin disease is recommended before considering a change in the TNF antagonist.19 However, the efficacy of such strategy remains to be proven. In our study, psorisias de novo led to adalimumab withdrawal in three of six patients despite conventional psoriasis treatment.

Collectively, our findings suggest that adalimumab therapy may be effective in the long term in patients with luminal and/or fistulizing CD who previously responded to infliximab and then lost response or became intolerant. Its safety profile needs to be investigated in larger series of patients. However, our results should be interpreted with caution due to the lack of placebo arm and the retrospective design of the study. A randomized controlled trial is necessary to investigate further the long-term efficacy and safety profile of adalimumab in patients with CD who had failure to infliximab. Our data also underscore the urgent need to develop novel biological therapies in CD refractory to TNF antagonists.20

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Declaration of personal interests: LPB has served as a speaker for Centocor, a consultant for Abbott Laboratories and UCB Pharma and has received research funding from UCB Pharma. AO, AB, JBC, LS, IT, MB, TB and MAB declare no conflict of interest. Declaration of funding interests: None.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References